Brain derived neurotrophic factor (BDNF) is neuroprotective, promotes axonal growth, and has been suggested to play roles in learning and counteracting depression. Increasing BDNF levels might, therefore, provide a means for treating various brain disorders. Recent work by the applicants discovered that positive modulators of AMPA-type glutamate receptors ('ampakines') induce BDNF expression. Ampakines cross the blood-brain barrier and have had minimal side effects in animal studies and clinical trials. Thus, they provide a plausible means for manipulating BDNF expression in brain. However, additional studies found that prolonged applications (24-48 h) cause BDNF induction to become refractory to treatment and led to a depression of fast excitatory responses suggesting that there may be a loss of glutamate receptor activity. Preliminary studies confirmed that prolonged ampakine treatment causes a loss of surface AMPA receptors. To obviate this problem, the applicants developed an on/off ampakine treatment regimen that sustains elevated BDNF levels (20-fold) for several days. The Program Project builds on these results and will address three broad objectives: 1) Identify cellular pathways through which ampakines up-regulate BDNF, induce refractoriness, and down-regulate fast, excitatory transmission; 2) Test if endogenous BDNF effects are similar to those of exogenous BDNF application; 3) Determine if up-regulation is neuroprotective. Project 1 will devise treatment regimens for optimally inducing BDNF, test if increased BDNF is associated with increased BDNF signaling and test the hypothesis that increased BDNF levels protect against ischemia. Project 2 will characterize the time course of ampakine-induced depression of synaptic responses and the hypothesis that this is due to a down regulation of AMPA receptors. Project 3 will compare the effects of exogenous BDNF with increases in endogenous BDNF on several physiological measures including transmitter release, synaptic plasticity, and cholinergically driven EEG rhythms. The possibility that BDNF interacts with integrin adhesion receptors to produce its effects will also be examined. Project 4 will use a mouse model pertinent to Alzheimer's disease (ApoE -/- mice) to test if endogenous BDNF counteracts age-related pathologies including neurofibrillary tangle formation and amyloid toxicity. Effects of BDNF on cholinergic innervation will also be examined. The four projects will use the same experimental preparations, treatments and core facilities. The program is expected to provide new insights into the regulation of excitatory receptors and neurotrophin expression. It could also provide foundations for a new therapeutic strategy for treatment of neuropsychiatric and neuropathological disorders.